DEVELOPMENT OF STANDARDS FOR FACTORS VIII AND IX

因素 VIII 和 IX 的标准制定

• 批准号: 6161369
• 负责人: T J LYNCH
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6161369
• 关键词: coagulation factor IX; coagulation factor VIII; drug quality /standard; immunoaffinity chromatography; recombinant proteins; western blottings

Potency standards for coagulation factors VIII (Antihemophilic Factor) and IX are needed to control the manufacture of these licensed products and to permit clinical assessment of their pharmacokinetics in patients. CBER has historically provided working standards for both products. In addition, it is desirable to establish standards that are recognized internationally in order to harmonize potency definitions and manufacturing requirements. A new U.S. standard for Factor Ix has been established and adopted by the European Pharrnacopoeia (EP) and World Health Organization (WHO). The standard was selected from among four intermediate- and high-purity factor IX preparations from four U.S. manufacturers. The selection was based on studies conducted at CBER that established the parallelism of dose- response curves for the standard and test materials; linearity of dose- response over a wide range of concentrations; inter-assay and intra-assay variability; physical integrity; and short-term stability. The selected factor Ix standard was filled into 25,000 glass vials, each containing approximately Il IU. The factor IX standard was then calibrated in a multicenter, international study involving 36 laboratories and assigned a value of 10.7 IU. The standard was accepted formally by the EP and the Expert Committee on Biological Standardization of the WHO in October, 1996. The standard is now available through these organizations and from CBER. Six candidates for a new U.S. factor VIII standard, derived from four U.S. manufacturers and including both plasma-derived and recombinant preparations, were initially evaluated by CBER. Each candidate was assessed for the same criteria indicated above and for consistency of results between two commonly used potency assays: the one-stage plasma assay and the chromogenic assay. Two candidates having satisfactory properties were selected for further evaluation in a multicenter, international study involving 18 laboratories, which was completed in early 1997. One candidate material was superior with respect to its unbiased, equivalent results in the one-stage and chromogenic assays, but had been lyophilized to an unacceptably high moisture content. This would likely have an adverse effect on stability if uncorrected. No reason for the high residual moisture has been identified, so an additional pilot fill is currently planned. In early 1997, the contractor who was to perform the filling and lyophilization of this standard informed CBER that changes in its technical staff made it impossible to continue with the project. An alternative form with the requisite capacity is currently being sought.

凝血因子VIII（抗亲密因子）和 需要IX来控制这些许可产品的制造和 允许对患者的药代动力学进行临床评估。 Cber有 历史上为这两种产品提供了工作标准。另外，它 希望建立在国际上认可的标准 为了协调效力定义和制造要求。一个 美国第IX因子的新标准已建立和采用 欧洲Pharrnacopoeia（EP）和世界卫生组织（WHO）。这 从四个中间和高纯度因子中选择了标准 来自美国四个制造商的IX准备工作。选择是基于 在CBER进行的研究确定了剂量的并行性 标准材料和测试材料的响应曲线；剂量的线性 在广泛浓度的响应中；间 - 测定内部 可变性；身体完整性；和短期稳定性。选定的 第IX标准因子被填充为25,000个玻璃小瓶，每个玻璃瓶都包含 大约il iu。然后将因子IX标准在A中校准 多中心，国际研究，涉及36个实验室，并分配了 值10.7 iu。该标准被EP正式接受 10月，WHO生物标准化专家委员会， 1996年。现在可以通过这些组织以及从 CBER。六个候选人是新的美国第VIII标准，源自 四个美国制造商，包括等离子衍生和重组 制剂最初是通过CBER评估的。每个候选人都是 根据上面指定的相同标准进行评估，并为 两种常用的效力测定之间的结果：单阶段等离子体 测定和成色测定。两个候选人令人满意 选择属性以在多中心进行进一步评估， 国际研究涉及18个实验室，该研究完成 1997年初。一项候选材料相对于其材料优越 公正的，等效的结果是单阶段和发色的测定，但 被冻干至不可接受的水分含量。这会 如果未校正，可能会对稳定性产生不利影响。没有理由 已经确定了高剩余水分，因此额外的飞行员 目前计划填充。在1997年初，承包商 执行此标准的通知CBER的填充和冻干 其技术人员的变化使得无法继续 项目。目前具有必要能力的替代表格 被寻求。